EP0699440A1 - Use of a ascorbyl tocopheryl phosphate for the manufacture of a medicament for the treatment of pancreatitis - Google Patents

Use of a ascorbyl tocopheryl phosphate for the manufacture of a medicament for the treatment of pancreatitis Download PDF

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Publication number
EP0699440A1
EP0699440A1 EP95112104A EP95112104A EP0699440A1 EP 0699440 A1 EP0699440 A1 EP 0699440A1 EP 95112104 A EP95112104 A EP 95112104A EP 95112104 A EP95112104 A EP 95112104A EP 0699440 A1 EP0699440 A1 EP 0699440A1
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Prior art keywords
pancreatitis
compound
phospholipase
treatment
therapeutic composition
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EP95112104A
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German (de)
French (fr)
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EP0699440B1 (en
Inventor
Kazumi Ogata
Takahiro Sakaue
Shinya Ogino
Sachiko Matsuura
Rie Nagao
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Senju Pharmaceutical Co Ltd
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Senju Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin

Definitions

  • This invention relates to a useful therapeutic composition for pancreatitis. More particularly, this invention relates to a useful therapeutic composition for pancreatitis which comprises an ascorbyl tocopheryl phosphate compound or a pharmacologically acceptable salt thereof.
  • pancreatic phospholipase A2 type I
  • membrane-bound and secretion type phospholipase A2 type II
  • pancreatic phospholipase A2 is one of the digestive enzymes synthesized in the pancreas and secreted into pancreatic juice.
  • Pancreatic phospholipase A2 is activated by trypsin, a proteolytic enzyme, in the duodenum and decomposes the phospholipids blended with the bile and solubilized.
  • pancreatic phospholipase A2 readily decomposes the cell membrane comprised of phospholipids, the lyso compounds produced in this process show high cytotoxicity. Therefore, pancreatic phospholipase A2 has been a focus of attention in connection with the onset and exacerbation of acute pancreatitis.
  • pancreatic phospholipase A2 finds its way into the circulation at the acme of pancreatitis to induce severe cytopatic effects.
  • citicholine is known as a drug having such a pharmacologic action.
  • type II phospholipase A2 non-pancreatic type which is detected at high levels in the exudates at inflammation sites is generally considered to be deeply involved in inflammation.
  • the mechanism of its inflammatory actions is generally visualized as the type II phospholipase A2-catalyzed production of arachidonic acid from the phospholipids of, for example, the cell membrane which is followed by both the cyclooxygenase pathway leading to prostaglandines (PG) and the lypoxygenase pathway leading to leukotrienes (LT).
  • Steroidal drugs are known to inhibit type II phospholipase A2 and, hence act as antiinflammatory agents blocking both of the pathways.
  • type I and type II phospholipase A2 are much different in biochemical properties but in the field of medicine there is not known a drug which sufficiently inhibits both of type I phospholipase A2 which is associated with pancreatitis and type II phospholipase A2 (non-pancreatic type) which is involved in inflammation.
  • This invention provides a very useful therapeutic composition for pancreatitis which comprises a phosphoric diester compound or a pharmacologically acceptable salt thereof.
  • This invention is directed to a therapeutic composition for pancreatitis which comprises a phosphoric diester compound of the following formula or a pharmacologically acceptable salt thereof (hereinafter referred to as the compound) wherein R1 and R2 are the same or different and each represents hydrogen or methyl.
  • the compound for use in the therapeutic composition for pancreatitis according to this invention can be synthesized by the processes described in U.S. Patent No. 4,564,686 or 4,914,197, among others.
  • the compound for use in the therapeutic composition for pancreatitis according to this invention has found application not only as an antiinflammatory drug, referred to above, but also as an anticataract drug, a prophylactic and therapeutic drug for climacteric disturbance, a skin-beautifying cosmetic (U.S. Patent No. 4,564,686), an antiulcer drug (U.S. Patent No. 4,888,329) and a prophylactic and therapeutic drug for ischemic disorder in organs (U.S. Patent No. 4,948,786), among a diversity of uses.
  • the compound for use in the therapeutic composition for pancreatitis according to this invention may be a free compound or a pharmacologically acceptable salt thereof.
  • the pharmacologically acceptable salt typically includes salts with alkali metals such as sodium, potassium, etc. and salts with alkaline earth metals such as calcium, magnesium, and so on. However, any other salts can likewise be employed only if it is pharmacologically acceptable.
  • the therapeutic composition for pancreatitis according to this invention may contain one or more species of the present compound according to the intended use and need.
  • the compound as the active ingredient of the therapeutic composition for pancreatitis according to this invention is a safe compound with only a very low toxic potential and can, therefore, be used for accomplishing the above-mentioned object of this invention
  • LD50 of L-ascorbyl DL- ⁇ -tocopheryl phosphate potassium (hereinafter referred to briefly as EPC-K) is ⁇ 5 g/kg p. o. (rats), ⁇ 100 mg/kg i.v. (rats)].
  • the therapeutic composition of this invention can be administered either orally or parenterally.
  • the dosage form in which the therapeutic composition of this invention can be provided includes solid preparations such as tablets, granules, powders, capsules, etc. and liquid preparations such as injections, all of which can be manufactured by the established pharmaceutical procedures.
  • These dosage forms may contain a variety of additives which are commonly employed, such as excipients, binders, reabsorption promoters, buffers, surfactants, solubilizer, preservatives, emulsifiers, isotonizing agents, stabilizers, pH control agents, etc., each in a suitable amount or proportion.
  • the dosage of the present compound for use as a therapeutic drug for pancreatitis is dependent on species of the compound, the patient's age, and body weight, clinical manifestations that must be controlled and dosage form, etc. but taking an injection as an example, about 1 mg to about 100 mg per adult man can be administered once a day and in the case of an oral preparation, about 10 mg to about 1,000 mg per adult man be administered a few times a day.
  • the therapeutic composition of this invention may further contain one or more other therapeutic drugs for pancreatitis and/or other kinds of pharmacologically active ingredients.
  • the therapeutic efficacy of the compound was tested in ethionine-induced pancreatitis which is a model of severe human pancreatitis.
  • the efficacy evaluation was based on the degree of inhibition of the release of amylase into blood which is an indicator of pancreatitis.
  • the serum amylase level in the distilled water group was not elevated at all till 24 hours after the beginning of intake of ethionine-supplemented food but subsequently rose, significantly as compared with the untreated group, to 41342 ⁇ 16494 (mU/ml) at 48 hours.
  • the serum amylase level at 48 hours after the beginning of intake of ethionine-supplemented food was 16257 ⁇ 9763 (mU/ml). This level represents a significant inhibition of serum amylase elevation compared with the distilled water group, and is almost within the normal range.
  • the 48-hour amylase level in the group treated with camostat monomethanesulfonate was 36288 ⁇ 13921 (mU/ml), showing no inhibitory effect on amylase elevation.
  • EPC-K 100mg Lactose 75mg Starch 20mg Polyethylene glycol 6000 5mg
  • the above ingredients per tablet are mixed in the conventional manner to provide a tablet.
  • the tablet may be sugar-coated.
  • the above ingredients are mixed and filtered through a bacterial filter in the routine manner.
  • the filtrate is aseptically distributed into glass ampules, 5 ml per ampule, to provide an injection.
  • the pharmaceutical composition of this invention can be used with advantage in the prevention and treatment of pancreatitis.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

This invention provides a therapeutic composition for pancreatitis which comprises a phosphoric diester compound of the following formula or a pharmacologically acceptable salt thereof
Figure imga0001
wherein R₁ and R₂ are the same or different and each represents hydrogen or methyl.
The pharmaceutical composition of this invention can be used with advantage in the prevention and treatment of pancreatitis.

Description

    FIELD OF THE INVENTION
  • This invention relates to a useful therapeutic composition for pancreatitis. More particularly, this invention relates to a useful therapeutic composition for pancreatitis which comprises an ascorbyl tocopheryl phosphate compound or a pharmacologically acceptable salt thereof.
    • BACKGROUND OF THE INVENTION
  • In man, there exists not only pancreatic phospholipase A₂ (PLA₂) (type I) but also membrane-bound and secretion type phospholipase A₂ (type II). These types of phospholipase A₂ are widely divergent in biochemical properties.
  • Among them, pancreatic phospholipase A₂ is one of the digestive enzymes synthesized in the pancreas and secreted into pancreatic juice. Pancreatic phospholipase A₂ is activated by trypsin, a proteolytic enzyme, in the duodenum and decomposes the phospholipids blended with the bile and solubilized. While pancreatic phospholipase A₂ readily decomposes the cell membrane comprised of phospholipids, the lyso compounds produced in this process show high cytotoxicity. Therefore, pancreatic phospholipase A₂ has been a focus of attention in connection with the onset and exacerbation of acute pancreatitis. It is generally postulated that since, in man, there is no inhibitor of pancreatic phospholipase A₂ activity, pancreatic phospholipase A₂ finds its way into the circulation at the acme of pancreatitis to induce severe cytopatic effects. As a drug having such a pharmacologic action, citicholine is known.
  • Meanwhile, type II phospholipase A₂ (non-pancreatic type) which is detected at high levels in the exudates at inflammation sites is generally considered to be deeply involved in inflammation. The mechanism of its inflammatory actions is generally visualized as the type II phospholipase A₂-catalyzed production of arachidonic acid from the phospholipids of, for example, the cell membrane which is followed by both the cyclooxygenase pathway leading to prostaglandines (PG) and the lypoxygenase pathway leading to leukotrienes (LT). Steroidal drugs are known to inhibit type II phospholipase A₂ and, hence act as antiinflammatory agents blocking both of the pathways.
  • Thus, type I and type II phospholipase A₂ are much different in biochemical properties but in the field of medicine there is not known a drug which sufficiently inhibits both of type I phospholipase A₂ which is associated with pancreatitis and type II phospholipase A₂ (non-pancreatic type) which is involved in inflammation.
  • Paying attention to inhibition of pancreatic phospholipase A₂, the inventors of this invention did intensive research. As a result, they discovered that an ascorbyl tocopheryl phosphate compound which is already known as an antiinflammatory agent having phospholipase A₂ inhibitory activity (U.S. Patent No. 4,914,197) is of value as a therapeutic drug for pancreatitis by virtue of its pancreatic phospholipase A₂ inhibitory action. This invention has been developed on the basis of the above finding.
  • This invention provides a very useful therapeutic composition for pancreatitis which comprises a phosphoric diester compound or a pharmacologically acceptable salt thereof.
    • SUMMARY OF THE INVENTION
  • This invention, therefore, is directed to a therapeutic composition for pancreatitis which comprises a phosphoric diester compound of the following formula or a pharmacologically acceptable salt thereof (hereinafter referred to as the compound)
    Figure imgb0001
    wherein R₁ and R₂ are the same or different and each represents hydrogen or methyl.
    • DETAILED DESCRIPTION OF THE INVENTION
  • The compound for use in the therapeutic composition for pancreatitis according to this invention can be synthesized by the processes described in U.S. Patent No. 4,564,686 or 4,914,197, among others.
  • The compound for use in the therapeutic composition for pancreatitis according to this invention has found application not only as an antiinflammatory drug, referred to above, but also as an anticataract drug, a prophylactic and therapeutic drug for climacteric disturbance, a skin-beautifying cosmetic (U.S. Patent No. 4,564,686), an antiulcer drug (U.S. Patent No. 4,888,329) and a prophylactic and therapeutic drug for ischemic disorder in organs (U.S. Patent No. 4,948,786), among a diversity of uses.
  • However, even the above-mentioned U.S. Patent No. 4,914,197 describing the usefulness of this compound as an antiinflammatory drug mentions simply that the compound has activity to inhibit phospholipase A₂ of the rat gastric mucosal origin and contains no information at all about its pancreatic phospholipase A₂ inhibitory activity which is a useful pharmacologic action for the treatment of pancreatitis. Therefore, it could never be easily conceived of that the very compound might be of use as a therapeutic drug for pancreatitis.
  • The compound for use in the therapeutic composition for pancreatitis according to this invention may be a free compound or a pharmacologically acceptable salt thereof. The pharmacologically acceptable salt typically includes salts with alkali metals such as sodium, potassium, etc. and salts with alkaline earth metals such as calcium, magnesium, and so on. However, any other salts can likewise be employed only if it is pharmacologically acceptable.
  • The therapeutic composition for pancreatitis according to this invention may contain one or more species of the present compound according to the intended use and need.
  • The compound as the active ingredient of the therapeutic composition for pancreatitis according to this invention is a safe compound with only a very low toxic potential and can, therefore, be used for accomplishing the above-mentioned object of this invention [LD₅₀ of L-ascorbyl DL-α-tocopheryl phosphate potassium (hereinafter referred to briefly as EPC-K) is ≧ 5 g/kg p. o. (rats), ≧ 100 mg/kg i.v. (rats)].
  • The therapeutic composition of this invention can be administered either orally or parenterally. The dosage form in which the therapeutic composition of this invention can be provided includes solid preparations such as tablets, granules, powders, capsules, etc. and liquid preparations such as injections, all of which can be manufactured by the established pharmaceutical procedures. These dosage forms may contain a variety of additives which are commonly employed, such as excipients, binders, reabsorption promoters, buffers, surfactants, solubilizer, preservatives, emulsifiers, isotonizing agents, stabilizers, pH control agents, etc., each in a suitable amount or proportion.
  • The dosage of the present compound for use as a therapeutic drug for pancreatitis is dependent on species of the compound, the patient's age, and body weight, clinical manifestations that must be controlled and dosage form, etc. but taking an injection as an example, about 1 mg to about 100 mg per adult man can be administered once a day and in the case of an oral preparation, about 10 mg to about 1,000 mg per adult man be administered a few times a day.
  • Unless contrary to the spirit and object of this invention, the therapeutic composition of this invention may further contain one or more other therapeutic drugs for pancreatitis and/or other kinds of pharmacologically active ingredients.
    • EXAMPLES
  • The following examples and formulation examples are further illustrative of this invention.
    • Example 1 Effect of the present compound on ethionine-induced severe pancreatitis
  • The therapeutic efficacy of the compound was tested in ethionine-induced pancreatitis which is a model of severe human pancreatitis. The efficacy evaluation was based on the degree of inhibition of the release of amylase into blood which is an indicator of pancreatitis.
    • Test substances:
    • (1) Investigational substance:
         L-Ascorbyl DL-α-tocopheryl phosphate potassium (briefly, EPC-K)
         141 mg/10 ml/kg, p.o.
    • (2) Control substances:
         Distilled water 10 ml/kg, p.o.
         Camostat monomethanesulfonate (Ono Pharmaceutical)
         100 mg/10 ml/kg, p.o.
    Animals used: Thirty female BALB/c mice weighing about 18 g as purchased from Japan SLC were used in this experiment. The mice were accommodated in an animal room controlled at 24± 4°C and 55± 15% R. H. and while the animals in the ethionine-induced pancreatitis groups were given low-choline, 0.5% ethionine-supplemented food (prepared by SLC) ad libitum, the animals in the untreated control group were given Labo MR Stock (tradename) (Nihon Nosan Kogyo) ad libitum. Water was freely available for animals in the ethionine pancreatitis groups and the untreated group. The mice were deprived of food 12 hours before commencement of feeding.
    Method: Each test substance was administered 12 hours after the beginning of intake of ethionine-supplemented food. Blood sampling was made 24 and 48 hours after the beginning of intake of ethionine-supplemented food and the serum amylase levels were determined.
    Results: The results are presented in Table 1. Table 1
    Effect of the compound on the elevation of serum amylase in ethionine-induced pancreatitis
    Group No. of cases 0 Hr 24 Hr 48 Hr
    Distilled water 8 14023± 1383 12368± 1853 41342± 16494
    EPC-K 8 14573± 3132 12926± 2217 16257± 9763*1
    Camostat monomethanesulfonate 7 13978± 1012 12628± 1542 36288± 13921
    Untreated 7 13386± 1394 16376± 1558 13029± 1950*1
    Each value is the mean ± S. E. All the values are in international units (mU/ml).
    Significantly different from the distilled water group: *1; p<0.01.
  • As shown in Table 1, the serum amylase level in the distilled water group was not elevated at all till 24 hours after the beginning of intake of ethionine-supplemented food but subsequently rose, significantly as compared with the untreated group, to 41342± 16494 (mU/ml) at 48 hours. In the group treated with the compound, the serum amylase level at 48 hours after the beginning of intake of ethionine-supplemented food was 16257± 9763 (mU/ml). This level represents a significant inhibition of serum amylase elevation compared with the distilled water group, and is almost within the normal range. On the other hand, the 48-hour amylase level in the group treated with camostat monomethanesulfonate was 36288± 13921 (mU/ml), showing no inhibitory effect on amylase elevation.
  • It is clear from the above results that the present compound is superior to camostat monomethanesulfonate, a commercial therapeutic drug for pancreatitis, in the therapeutic effect on pancreatitis.
    • Formulation Example 1 Oral tablet
  • EPC-K 100mg
    Lactose 75mg
    Starch 20mg
    Polyethylene glycol 6000 5mg
  • The above ingredients per tablet are mixed in the conventional manner to provide a tablet. Where necessary, the tablet may be sugar-coated.
    • Formulation Example 2 injection
  • EPC-K 200mg
    Mannitol 5.0 g
    1N-Sodium hydroxide q.s.
    Distilled water To make 100 ml
    pH6.5
  • The above ingredients are mixed and filtered through a bacterial filter in the routine manner. The filtrate is aseptically distributed into glass ampules, 5 ml per ampule, to provide an injection.
  • The pharmaceutical composition of this invention can be used with advantage in the prevention and treatment of pancreatitis.

Claims (1)

  1. A therapeutic composition for pancreatitis which comprises a phosphoric diester compound of the following formula or a pharmacologically acceptable salt thereof
    Figure imgb0002
     wherein R₁ and R₂ are the same or different and each represents hydrogen or methyl.
EP95112104A 1994-08-05 1995-08-01 Use of a ascorbyl tocopheryl phosphate for the manufacture of a medicament for the treatment of pancreatitis Expired - Lifetime EP0699440B1 (en)

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JP184282/94 1994-08-05
JP18428294 1994-08-05

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EP0699440A1 true EP0699440A1 (en) 1996-03-06
EP0699440B1 EP0699440B1 (en) 1998-11-25

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US (1) US5650404A (en)
EP (1) EP0699440B1 (en)
KR (1) KR960006915A (en)
AT (1) ATE173626T1 (en)
CA (1) CA2152693A1 (en)
DE (1) DE69506197T2 (en)
ES (1) ES2124477T3 (en)
TW (1) TW317500B (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002026238A1 (en) * 2000-09-26 2002-04-04 Vital Health Sciences Pty Ltd. Phosphate derivative supplements
WO2007070981A1 (en) * 2005-12-23 2007-06-28 Vital Health Sciences Pty Ltd Compounds having cytokine modulating properties
EP2559432A1 (en) * 2010-04-13 2013-02-20 Limited Liability Company «GamaVetFarm» Means for the prophylaxis and treatment of acute and chronic pancreatitis
US10071030B2 (en) 2010-02-05 2018-09-11 Phosphagenics Limited Carrier comprising non-neutralised tocopheryl phosphate
US10188670B2 (en) 2011-03-15 2019-01-29 Phosphagenics Limited Composition
US10973761B2 (en) 2015-12-09 2021-04-13 Phosphagenics Limited Pharmaceutical formulation
US11753435B2 (en) 2016-12-21 2023-09-12 Avecho Biotechnology Limited Process

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US6703384B2 (en) * 1998-09-23 2004-03-09 Research Development Foundation Tocopherols, tocotrienols, other chroman and side chain derivatives and uses thereof
CA2345079C (en) * 1998-09-23 2011-06-21 Research Development Foundation Tocopherols, tocotrienols, other chroman and side chain derivatives and uses thereof
NZ520798A (en) * 2000-02-11 2004-05-28 Res Dev Foundation Tocopherols, tocotrienols, other chroman and side chain derivatives and uses thereof
AUPR549901A0 (en) 2001-06-06 2001-07-12 Vital Health Sciences Pty Ltd Topical formulation containing tocopheryl phosphates
EP1420797A4 (en) 2001-07-27 2005-03-02 Vital Health Sciences Pty Ltd Dermal therapy using phosphate derivatives of electron transfer agents
US20030236301A1 (en) * 2001-12-19 2003-12-25 Bob Sanders Liposomal delivery of vitamin E based compounds
AU2002950713A0 (en) 2002-08-09 2002-09-12 Vital Health Sciences Pty Ltd Carrier
WO2005084678A1 (en) 2004-03-03 2005-09-15 Vital Health Sciences Pty Ltd Alkaloid formulations
ES2557475T3 (en) 2005-06-17 2016-01-26 Vital Health Sciences Pty Ltd. A carrier comprising one or more di- and / or monophosphate derivatives of electron transfer agents
ES2829386T3 (en) 2010-03-30 2021-05-31 Phosphagenics Ltd Transdermal administration patch
EP4034137A4 (en) * 2019-09-27 2023-09-20 Duke University Compositions and methods for the prevention and treatment of pancreatitis

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EP0236120A2 (en) * 1986-03-04 1987-09-09 Senju Seiyaku Kabushiki Kaisha also known as Senju Pharmaceutical Co. Ltd. Mixed phosphoric diesters, preparation thereof, and use thereof as antiinflammatory agents
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G.ZÖCH ET AL.: "Effekt von p-Bromphenacylbromid, einem Phospholipase A-Hemmer, bei experimenteller akuter Pankreatitis der Ratte", RES.EXP.MED., vol. 184, no. 3, pages 179 - 189 *
H.T.TYKKÄ ET AL.: "A randomized double-blind study using CaNa2EDTA, a phospholipase A2 inhibitor, in the management of human acute pancreatitis", SCAND. J. GASTROENTEROL., vol. 20, no. 1, pages 5 - 12 *
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J.M.BRAGANZA ET AL.: "Recalcitrant pancreatitis: eventual control by antioxidants", PANCREAS, vol. 2, no. 4, pages 489 - 494 *
KAKUJI TOJO ET AL.: "Bioconversion of a provitamin to vitamins C and E in skin", J.SOC.COSMET.CHEM., vol. 38, no. 5, pages 333 - 339 *
RONALD ANDERSON ET AL.: "Alpha-tocopherol prevents cyclosporin A-mediated activation of phospholipase A2 and inhibition of Na+, K+-adenosine triphosphatase activity in cultured hamster renal tubular cells", TOXICOLOGY AND APPLIED PHARMACOLOGY, vol. 125, no. 2, pages 176 - 183, XP024880446, DOI: doi:10.1006/taap.1994.1062 *
S. UDEN ET AL.: "Rationale for antioxidant therapy in pancreatitis and cystic fibrosis", ADV.EXP. MED. BIOL., vol. 264, pages 555 - 572, XP009070791 *
T.J. NEVALAINEN: "The role of phospholipase A2 in acute pancreatitis", Z. MED. LAB. DIAGN., vol. 30, no. 6, pages 299 - 303 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002026238A1 (en) * 2000-09-26 2002-04-04 Vital Health Sciences Pty Ltd. Phosphate derivative supplements
WO2007070981A1 (en) * 2005-12-23 2007-06-28 Vital Health Sciences Pty Ltd Compounds having cytokine modulating properties
US10071030B2 (en) 2010-02-05 2018-09-11 Phosphagenics Limited Carrier comprising non-neutralised tocopheryl phosphate
EP2559432A1 (en) * 2010-04-13 2013-02-20 Limited Liability Company «GamaVetFarm» Means for the prophylaxis and treatment of acute and chronic pancreatitis
EP2559432A4 (en) * 2010-04-13 2015-04-08 Ltd Liability Company Gamavetfarm Means for the prophylaxis and treatment of acute and chronic pancreatitis
US10188670B2 (en) 2011-03-15 2019-01-29 Phosphagenics Limited Composition
US10973761B2 (en) 2015-12-09 2021-04-13 Phosphagenics Limited Pharmaceutical formulation
US11753435B2 (en) 2016-12-21 2023-09-12 Avecho Biotechnology Limited Process

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EP0699440B1 (en) 1998-11-25
ES2124477T3 (en) 1999-02-01
KR960006915A (en) 1996-03-22
DE69506197T2 (en) 1999-04-15
DE69506197D1 (en) 1999-01-07
US5650404A (en) 1997-07-22
CA2152693A1 (en) 1996-02-06
ATE173626T1 (en) 1998-12-15
TW317500B (en) 1997-10-11

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